Human immunodeficiency virus (HIV) protease inhibitors (Pis) have been used successfully in highly active anti-retroviral therapy (HAART) for HIV infection. Incorporation of HIV Pis in HAART causes profound and sustained suppression of viral replication, significantly reduces the morbidity and mortality, and prolongs the lifespan of patients with HIV infection. However, more than 50% of patients receiving HAART develop lipid abnormalities and diabetes, which are well-known risk factors for serious cardiovascular complications including endothelial dysfunction and atherosclerosis. Although the mechanism underlying HIV Pi-induced atherosclerosis remains to be fully identified, an increasing body of evidence suggests that multiple mechanisms may be involved, and individual Pis may have different effects on lipid metabolism. The development of other therapeutic interventions to counteract the HIV Pi-associated complications are especially urgent, and this development is the long-term objective of this application. Atherosclerosis is a chronic inflammatory disease and macrophages play a critical role in the initiation and progression of atherosclerotic lesions. Both inflammation and apoptosis are two major events in the pathophysiology of atherosclerosis. We have recently demonstrated that HIV Pis activate the unfolded protein response (UPR), induce apoptosis, and promote foam cell formation in macrophages. Berberine (BBR), an isoquinoline alkaloid isolated from many medicinal herbs, has significant anti-inflammatory activity and recently has been identified as a novel cholesterol-lowering drug. Our preliminary studies also indicate that BBR strongly inhibits HIV Pi-induced UPR activation, foam cell formation, and TNF-a and IL-6 release in macrophages. Based on these observations, we HYPOTHESIZE that BBR is able to prevent HIV Pi-induced atherosclerosis by inhibiting the UPR activation and the inflammatory response in macrophages. Three specific aims are proposed to test the hypothesis. Aim#1: To elucidate the cellular/molecular mechanisms by which BBR inhibits HIV Pi-induced UPR activation in macrophages. Aim#2: To determine cellular/molecular mechanisms by which BBR inhibits HIV Pi-induced TNF-a and IL-6 synthesis in macrophages. Aim#3: To determine whether BBR is able to prevent the dyslipidemia and atherosclerosis induced by HIV Pis in an in vivo animal model. An increasing amount of attention has been paid to the use of complementary and alternative medicine (CAM) as a part of the treatment for HIV infection and the complications associated with HAART. Understanding the mechanisms by which BBR prevents HIV Pi- induced dyslipidemia and atherosclerosis is of great clinical importance. Completion of these specific aims will help identify and establish new therapeutic strategies for HIV infection.